This invention relates to a therapeutic composition useful for treatment of mucositis and methods for using the therapeutic composition.
Mucositis is a serious and often very painful disorder involving inflammation of the mucous membrane, with the inflammation often accompanied by infection and/or ulceration. Mucositis can occur at any of the different mucosal sites in the body. A nonlimiting list of examples of locations where mucositis can occur include mucosal sites in the oral cavity, esophagus, gastrointestinal tract, bladder, vagina, rectum, lung, nasal cavity, ear and orbita. Mucositis often develops as a side effect of cancer therapy, and especially as a side effect of chemotherapy and radiation therapy for the treatment of cancer. While cancerous cells are the primary targets of cancer therapies, other cell types can be damaged as well. Exposure to radiation and/or chemotherapeutics often results in significant disruption of cellular integrity in mucosal epithelium, leading to inflammation, infection and/or ulceration at mucosal sites.
As one example, oral mucositis (OM) is a painful and costly complication of some cancer therapies. The oral cavity is lined with mucosal epithelium, and exposure to radiation and/or chemotherapeutics results in the disruption of cellular integrity leading to the development of ulcerative lesions commonly referred to as oral mucositis. Oral mucositis is most prevalent in patient populations with head and neck malignancies being treated with radiation therapy. Oral mucositis usually occurs after the second week of radiation therapy, with severe symptoms usually resolving within six weeks following completion of therapy. It has been reported that this condition also affects approximately forty percent of patients undergoing chemotherapy, bone marrow transplantation or combinations thereof. Chemotherapeutic agents likely to cause oral mucositis include bleomycin, dactinomycin, doxorubicin, etoposide, floxuridine, 5-fluorouracil, hydroxyurea, methotrexate, mitomycin, vinblastine, vincristine, and vinorelbine. The risk of developing mucositis is markedly exacerbated when chemotherapeutic agents that typically produce mucosal toxicity are given in high doses, in frequent repetitive schedules, or in combination with ionizing irradiation (e.g., conditioning regimens prior to bone marrow transplant). The lesions induced by chemotherapeutic agents are clinically significant by about a week after treatment and the severity progresses to about day ten through twelve and begins to subside by day fourteen.
Oral mucositis appears to be a four-phase process: the primary phase is inflammatory/vascular in nature resulting in a cytokine release from the epithelium brought on by damage caused by radiation and/or chemotherapy. The second phase, referred to as the epithelial phase, is signaled by atrophy and ulceration of the mucosal epithelium. The third phase is defined as the ulcerative/bacterial phase represented by ulcerative lesions that are prone to bacterial infection further compromising the patients"" immune system. These painful lesions often limit a patient""s ability to eat and drink and in some cases require hospitalization. The presence of these lesions can also interrupt scheduled chemotherapy and/or radiation treatments. The last phase, the healing phase, is characterized by a proliferation and differentiation of epithelium as well as bacterial control.
Routine oral hygiene is extremely important in reducing the incidence and severity of mucositis. Oral hygiene methods include rinsing/irrigation and mechanical plaque removal. Although not entirely supported by controlled clinical trials, allopurinol mouthwash and vitamin E have been cited as agents that may decrease the severity of mucositis. Prophylaxis against fungal infections is commonly employed in an effort to treat oral mucositis and includes use of topical antifungal agents such as nystatin-containing mouthwashes and clotrimazole troches. Although topical antifungal prophylaxis and treatment may clear superficial oropharyngeal infections, topical agents tend not to be well absorbed and have not been demonstrated to be effective against more deeply invasive fungal infections, which typically involve the esophagus and lower gastrointestinal tract. For this reason, systemic agents are indicated for treating all except superficial fungal infections in the oral cavity.
Many different compounds have been evaluated for use as a prophylaxis and treatment of oral mucositis. Current therapies include cryotherapy (ice chips) to reduce pain and inflammation, analgesics to manage pain, and antibiotic therapy to control the opportunistic infection. Analgesics such as lidocaine mouthwashes are effective for short periods of time but within hours the pain and discomfort usually returns.
Chlorhexidine is a broad spectrum antimicrobial with activity against gram-positive and gram-negative organisms, yeast, and other fungal organisms. It also has the desirable properties of sustained binding to oral surfaces and minimal gastrointestinal (GI) absorption, thereby limiting adverse systemic effects. Its use in the prophylaxis of oral infections shows promise in reducing inflammation and ulceration, as well as in reducing oral microorganisms in high-risk patient groups. Other agents, such as allopurinol, leucovorin, vitamins, and growth factors, have been tried for the prevention of chemotherapy-induced mucositis. Use of a capsaicin-containing candy has also been advocated to desensitize pain receptors in the mouth. Also, studies utilizing nonsteroidal agents and coating agents, such as sucralfate (Carafate), have had conflicting results. Finally, claims that chlorhexidine (Peridex) reduces mucositis in both irradiated patients and leukemia patients receiving bone marrow transplants have not been verified. To date, none of these approaches has shown a significant impact.
Occurrence of mucositis at mucosal sites other than in the oral cavity in association with chemotherapy or radiation therapy are mechanistically similar to the occurrence of oral mucositis. For example, patients undergoing radiation therapy treatment for non-small cell lung cancer frequently develop esophagitis as a side effect of treatment. Esophagitis in this patient population can impede the progress of cancer treatment.
Given that a large number of patients suffer mucositis annually and patients undergoing cancer therapy often receive multiple cycles of chemotherapy and/or radiation therapy, there is a significant need for improved treatment of mucositis. The present invention is directed to this need.
In one aspect, the present invention provides a therapeutic composition for the treatment of mucositis. By treatment of mucositis, it is meant that the therapeutic composition is effective to prevent or reduce the incidence, severity and/or duration of the disease. The therapeutic composition comprises at least one pharmaceutical substance that, as formulated in the therapeutic composition, presents therapeutic effect in mammalian hosts, typically human hosts, for the treatment of mucositis, together with at least one biocompatible polymer that aids delivery of the pharmaceutical substance to the targeted mucosal site. One preferred embodiment of the therapeutic composition includes N-acetylcysteine as the pharmaceutical substance and a polyoxyalkylene block copolymer as the biocompatible polymer.
The therapeutic composition can be made with or without reverse-thermal viscosity behavior. For many applications, reverse-thermal viscosity behavior is beneficial to permit administration in a lower viscosity fluid form that tends to convert to a higher viscosity form following administration as the temperature of the therapeutic composition increases in the body. This also facilitates administration at a refrigerated temperature, which is soothing and refreshing to the host in a number of situations, such as for the treatment of mucosal surfaces in the oral cavity or esophagus. The biocompatible polymer will often be a reverse-thermal gelation polymer capable of imparting the desired reverse-thermal viscosity behavior to the therapeutic composition. Also, the therapeutic composition can be made in a variety of product forms, with different product forms being more desirable for targeting treatment to different mucosal sites. Also, in some applications it is desirable that the reverse-thermal viscosity behavior can include reverse-thermal gelation, in which case the therapeutic composition converts to a gel form as the temperature of the composition is increased from below to above a reverse-thermal gel transition temperature. When the therapeutic composition has reverse-thermal gelation properties, the therapeutic composition will preferably have a reverse-thermal gel transition temperature that is no higher than, and even more preferably lower than, the physiological temperature of the host. Depending upon the specific application, the therapeutic composition could be administered to the host at a cold temperature at which the therapeutic composition is in the form of a flowable medium, or at a temperature at which the therapeutic composition is in the form of a gel. When administered in the form of a gel, the therapeutic composition will often have a thick, pudding-like texture. Inside the body, the gel tends to break down as biological fluids dilute the therapeutic composition. But even with breakdown of the gel, significant amounts of the biocompatible polymer and pharmaceutical substance tend to adhere to mucosal surfaces to promote effective delivery of the pharmaceutical substance to treat the targeted mucosal site.
When treating for oral mucositis, the therapeutic composition is preferably administered in the form of a flowable medium with sufficient fluidity for use as a mouthwash that can be swished in the oral cavity to promote adhesion of the biocompatible polymer, and therefore also the pharmaceutical substance, to mucosal surfaces in the oral cavity. The therapeutic composition will typically include a carrier liquid (also referred to herein as a liquid vehicle), such as water, and the pharmaceutical substance and the biocompatible polymer are each dissolved or suspended in the carrier liquid when the therapeutic composition is in the flowable medium form for introduction into the oral cavity.
When treating for esophagitis, the composition will preferably have a very high viscosity as it is swallowed to promote a long residence time in the esophagus and effective coating of mucosal surfaces in the esophagus. In one embodiment, the therapeutic composition is in a thick, pudding-like form, typically a gel form, that can be spooned into the mouth and swallowed. In another preferred embodiment, the therapeutic composition is introduced into the oral cavity as a flowable medium that undergoes a viscosity increase as it warms and is swallowed. For esophageal applications, when the therapeutic composition is administered as a cold flowable medium, the therapeutic composition preferably has reverse-thermal gelation properties.
For targeting mucosal surfaces in the stomach, the therapeutic composition will preferably be in a form so that it can be readily swallowed to coat the mucosal surfaces in the stomach. Preferred embodiments include those noted for treatment of esophagitis.
For application to nasal mucosal surfaces, it is preferred that the therapeutic composition be sufficiently fluid so as to be nebulizable or otherwise sprayable to generate a nasal spray of the therapeutic composition that can be introduced into the nasal cavity. Preferably, the therapeutic composition is at a refrigerated temperature when sprayed and exhibits reverse-thermal viscosity behavior, so that it undergoes an increase in viscosity as it warms in the nasal cavity, thereby promoting adhesion to mucosal surfaces. For nasal applications, it is preferred that the therapeutic composition have reverse-thermal gelation properties.
For application to ocular mucosal surfaces, it is preferred that the therapeutic composition be sufficiently fluid to be administratable in the form of eye-drops, but the therapeutic composition should preferably not gel following administration of the eye drops.
For application to rectal or vaginal mucosal surfaces, the therapeutic composition is preferably in the form of a viscous gel when at physiological temperature. The therapeutic composition can be formulated to exhibit reverse-thermal viscosity behavior so that it is administrable in a refrigerated form at a lower viscosity and converts to a higher viscosity form, preferably a gel form, as the therapeutic composition warms following administration.
For application to pulmonary mucosal surfaces, the therapeutic composition should be sufficiently fluid immediately prior to administration to permit the therapeutic composition to be aerosolized, such as by a nebulizer, for administration by inhalation of the therapeutic composition in aerosol form.
For enhanced performance of the therapeutic composition, it is important that one or more of the components of the therapeutic composition are sufficiently bioadhesive to promote ready adhesion to mucosal surfaces, thereby promoting retention of the pharmaceutical substance adjacent the mucosal surface for effective delivery to the targeted mucosal site. In one preferred embodiment, the biocompatible polymer is bioadhesive, so that when the therapeutic composition is contacted with a mucosal surface, at least a portion of the biocompatible polymer readily adheres to the surface. Preferably, the biocompatible polymer and the pharmaceutical substance are closely associated with each other in the therapeutic composition such that when the biocompatible polymer adheres to a surface inside the oral cavity, the pharmaceutical substance also adheres to the surface along with the biocompatible polymer. This will often be the case when the carrier liquid is water and the biocompatible polymer has surfactant properties. In a preferred embodiment the surfactant properties of the biocompatible polymer enhance solubility of the pharmaceutical substance in the carrier liquid. In one embodiment, the therapeutic composition includes, in addition to the biocompatible polymer, a separate bioadhesive agent that enhances the bioadhesive properties of the therapeutic composition. The bioadhesive agent is frequently a second polymer having even greater bioadhesive properties.
In a further enhancement, the therapeutic composition may include a penetration enhancer, which aids rapid transport of the pharmaceutical substance across the mucosal epithelium. The therapeutic composition can also include other components that are compatible with the pharmaceutical substance and the biocompatible polymer.
In another aspect, the invention involves a therapeutic composition useful for treatment of mucositis at a mucosal site, with the composition comprising a sulfur-containing antioxidant. Such sulfur-containing anti-oxidants include those in which the sulfur is preferably present in a thiol, thioether, thioester, thiourea, thiocarbamate, disulfide, or sulfonium group. A particularly preferred sulfur-containing antioxidant is N-acetylcysteine.
In another aspect, the present invention involves use of the therapeutic composition, in any form and with any formulation, for treatment of mucositis.
In another aspect, a method is provided for delivering to a mucosal site a pharmaceutical substance for treatment of mucositis at a mucosal site, involving introduction into a host of a therapeutic composition of the invention. In one embodiment, the method involves introducing a therapeutic composition into the host, with the therapeutic composition comprising the pharmaceutical substance and a biocompatible polymer. After the therapeutic composition is introduced into the host, at least a portion of the biocompatible polymer and the pharmaceutical substance adhere to a mucosal surface at the mucosal site.
Both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide explanation of the invention as claimed. Other objects, advantages and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention.